Acute respiratory distress syndrome (ARDS) / diffuse alveolar damage (DAD)

Lung - nontumor
Other nonneoplastic disease
Acute respiratory distress syndrome (ARDS) / diffuse alveolar damage (DAD)

Authors: Akira Yoshikawa, M.D., Junya Fukuoka, M.D., Ph.D., Andrey Bychkov, M.D., Ph.D.

Topic Completed: 1 September 2017

Minor changes: 13 December 2019

Revised: 28 August 2018, last major update September 2017

Copyright: (c) 2003-2018, PathologyOutlines.com, Inc.

PubMed search: (Acute respiratory distress syndrome) ARDS (diffuse alveolar damage) DAD

Related topics: Acute fibrinous and organizing pneumonia

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Table of Contents

Cite this page: Yoshikawa, A. and Fukuoka, J. Acute respiratory distress syndrome (ARDS) / diffuse alveolar damage (DAD). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumordiffusealveolardamage.html. Accessed May 29th, 2020.

Definition / general

In 1994, the American European Consensus Conference (AECC) defined acute respiratory distress syndrome (ARDS) as "the acute onset of hypoxemia with bilateral infiltrates on frontal chest radiograph, with no evidence of left atrial hypertension" (AECC definition, Am J Respir Crit Care Med 1994;149:818)
In 2012, the ARDS Task Force revised the definition (Berlin definition, JAMA 2012;307:2526)
Diffuse alveolar damage (DAD) is manifested by injury to alveolar lining and endothelial cells, pulmonary edema, hyaline membrane formation and later by proliferative changes involving alveolar and bronchiolar lining cells and interstitial cells (Am J Pathol 1976;85:209)

Essential features

Acute and rapidly progressive hypoxia with bilateral pulmonary edema due to alveolar injury caused by pulmonary or systemic insults
40% die within 28 days from onset of ARDS, mainly due to septic shock and multiple organ dysfunction syndrome (MODS)
DAD is the most common morphological pattern of ARDS; however the clinical syndrome of ARDS is not synonymous with the pathologic diagnosis of DAD
DAD pattern is often characterized by hyaline membranes in acute phase but shows a wide variety of findings that makes the diagnosis challenging

Terminology

Previously known as "adult respiratory distress syndrome"
"Acute lung injury," an overlapping entity suggested in AECC definition, was removed from Berlin definition; the AECC definition of "acute lung injury non-ARDS" is compatible with Berlin definition of mild ARDS (JAMA 2012;307:2526)

ICD coding

Acute respiratory distress syndrome: J80

Epidemiology

Mean age 60 years old, varies from child to elderly
M:F = 3:2
Incidence of 5.0 to 78.9 per 100,000 person/year, varies by age (N Engl J Med 2005;353:1685, Intensive Care Med 2009;35:1352)
Incidence of ARDS in intensive care unit (ICU) (JAMA 2016;315:788)
- 10.4% of all ICU patients
- 67.2% of patients with acute hypoxemic respiratory failure
- ARDS was frequently undiagnosed (only 60.2% recognized by clinician) or late diagnosed (34.0% recognized at the time of criteria fulfillment)
Not all ARDS show DAD pattern
- Studies of open lung biopsy and autopsy found DAD in 56 - 58% and 45% of ARDS patients, respectively (Crit Care 2015;19:228, Am J Respir Crit Care Med 2013;187:761, Intensive Care Med 2015;41:222)

Sites

Bilateral lung without upper or lower predominance

Pathophysiology

Pathogenesis (N Engl J Med 2000;342:1334, Lancet 2016;388:2416):
- Exudative (acute) phase: 1 - 7 days
  - Neutrophil mediated inflammation damages the alveolar capillary barrier (alveolar epithelium and endothelium), increases its permeability and causes intra-alveolar hemorrhage and edema
  - Protein rich edema interacts with alveolar surfactants, resulting in decreased pulmonary compliance
  - Hyaline membranes are developed on alveolar wall where epithelium is denudated and disrupted
- Proliferative / organizing (subacute) phase: 1 - 3 weeks
  - Restoration of type II pneumocytes and subsequent differentiation into type I pneumocytes
  - Proliferation of myofibroblasts
  - Drainage of alveolar edema by restored type II pneumocytes
- Fibrotic (chronic) phase: after 3 weeks
  - Collagenous fibrosis in alveolar spaces and interstitium
  - Refractory rigidity of alveoli due to architectural remodeling
Pathophysiology of hypoxia
- Collapse of alveoli
- Increased right to left intrapulmonary shunt
- Decreased pulmonary compliance
  - Surfactant malfunction
  - Fibrosis
- Decreased diffusing capacity due to pulmonary edema
- Increased ventilation perfusion mismatch
- Increased pulmonary vascular resistance
Mechanism of ARDS to cause MODS is not clear
- Ventilator induced lung injury may play a critical role for upregulation of cytokines and eventual development of MODS (Curr Opin Crit Care 2011;17:1, Respir Care 2014;59:1422)

Etiology

Causes of pulmonary and extrapulmonary origin (see table below, N Engl J Med 2000;342:1334)
- Infection
  - Bacteria: Mycoplasma, Mycobacteria, Legionella, Rickettsia
  - Virus: influenza virus, herpes virus, cytomegalovirus, hantavirus
  - Fungi: Pneumocystis jirovecii
- Drug
  - Chemotherapeutic drugs: methotrexate, bleomycin, azathioprine, busulfan
  - Molecular targeted drugs
  - Gold
  - Amiodarone
  - Penicillamine
  - Nitrofurantoin
- Autoimmune disease
  - Polymyositis / dermatomyositis
    - Especially in clinically amyopathic dermatomyositis
  - Systemic lupus erythematosus
  - Scleroderma
  - Rheumatoid arthritis
  - Polyarteritis nodosa
  - Undifferentiated (subclinical) connective tissue disease
    - Often positive for serum anti MDA5 antibody (Medicine (Baltimore) 2012;91:220) or anti aminoacyl-transfer RNA synthetases (ARS) antibody (BMJ Case Rep 2016 Dec 9;2016, Tuberc Respir Dis (Seoul) 2016;79:188)
- Inhalation
  - Smoke
  - Sulfur dioxide
  - Oxygen
  - Nitrogen dioxide

Diagrams / tables

Causes of pulmonary and extrapulmonary origin
Direct lung injury	Indirect lung injury
Common causes Infectious pneumonia Aspiration of gastric contents	Common causes Sepsis Severe trauma or burn, especially with shock and multiple transfusions
Less common causes Pulmonary contusion Fat emboli Near drowning Inhalational injury (particle, gas) Reperfusion pulmonary edema, after lung transplantation or pulmonary embolectomy	Less common causes Cardiopulmonary bypass Drug Acute pancreatitis Autoimmune disease Transfusion related acute lung injury

Images hosted on other servers:

Normal and acute phase

Proliferative / organizing phase

Clinical features

Acute and progressive respiratory failure
- Usually starts 12 - 48 hours after the initial insult
- Shortness of breath; dyspnea on exertion followed by dyspnea at rest
- Hypoxia; PaO₂/FIO₂ ≤ 300 mm Hg
Often sepsis and MODS (JAMA 2016;315:788)
Respiratory dysfunction and physical disability may persist for months after remission of ARDS, with gradual improvement (N Engl J Med 2003;348:683)

Diagnosis

Diagnosis of ARDS is based on clinical manifestation and its severity is evaluated with ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FIO₂)
Berlin definition (JAMA 2012;307:2526)
- Timing
  - Within 1 week of a known clinical insult or new or worsening respiratory symptoms
- Chest imaging
  - Assessed by chest radiograph or computed tomography
  - Bilateral opacities, not fully explained by effusions, lobar / lung collapse or nodules
- Origin of edema
  - Respiratory failure not fully explained by cardiac failure or fluid overload
  - Need objective assessment (e.g. echocardiography) to exclude hydrostatic edema if no risk factor present
- Oxygenation (with positive end expiratory pressure [PEEP] or continuous airway pressure [CPAP] ≥ 5 cm H₂O)
  - Mild: 200 < PaO₂/FIO₂ ≤ 300 mm Hg
  - Moderate: 100 < PaO₂/FIO₂ ≤ 200 mm Hg
  - Severe: PaO₂/FIO₂ ≤ 100 mm Hg
Lung biopsy can be helpful for critical care and prognosis estimation for patients with ARDS
- Open lung biopsy provided a specific diagnosis for 84% of ARDS patients and an alternative treatment for 73% cases (Ann Thorac Surg 2014;98:1254)
- ARDS with DAD has poorer prognosis (see prognostic factors)
- Carefully consider biopsy if there is a high prediction for beneficial result and the risk of empirical therapy is not suitable or unsuccessful (Chest 2015;148:1073)

Laboratory

Arterial blood gas test
- Hypoxemia
- Ratio of pulse oximetric oxygen saturation to FIO₂ (SpO₂/FIO₂) may be helpful for diagnosis and follow up (Chest 2007;132:410)
  - SpO₂/FIO₂ of 235 ≈ PaO₂/FIO₂ of 200 (sensitivity: 85%, specificity: 85%)
  - SpO₂/FIO₂ of 315 ≈ PaO₂/FIO₂ of 300 (sensitivity: 91%, specificity: 56%)
Other blood tests
- Increased C reactive protein
- Increased procalcitonin in septic ARDS
- Increased ferritin (Am J Respir Crit Care Med 1999;159:1506)
- Increased KL-6
- Brain natriuretic peptide (BNP) test may helpful to distinguish ARDS and cardiogenic pulmonary edema (Chest 2007;131:964)
  - BNP ≤ 200 pg/ml is suggestive for ARDS (sensitivity: 40%, specificity: 91%)
  - BNP ≥ 1200 pg/ml is suggestive for cardiogenic pulmonary edema (sensitivity: 52%, specificity: 92%)

Radiology description

General
- Heterogeneous bilateral shadows due to pulmonary edema
- Must rule out atelectasis, pleural effusion and mass
- Takes 12 - 24 hours from onset to be apparent
Chest radiograph
- Exudative phase: ground glass opacity and consolidation with air bronchogram
- Proliferative / organizing and fibrotic phases: reticular shadow and volume reduction
Chest CT
- Exudative phase
  - Patchy to diffuse ground glass opacity with / without interlobular septal thickening
  - Dorsal consolidation due to infiltrate
- Proliferative / organizing phase
  - Ground glass opacity with bronchiolectasis and bronchiectasis
  - Volume reduction
- Fibrotic phase
  - Septal thickening and reticular shadow in ground glass opacity
  - Peripheral cystic and honeycomb-like lesion due to fibrosis

Prognostic factors

Septic shock and MODS account for 50% of death for patients with ARDS, while respiratory failure is responsible for 10 - 20% (Am J Respir Crit Care Med 2013;187:761, Chest 2005;128:525, Chest 1989;96:885, Clin Chest Med 2006;27:725)
First 7 - 10 days are the most relevant for the prognosis of ARDS (JAMA 2016;315:788)
- Of all ARDS patients, 93.1% developed ARDS in the first 48 hours
- Mortality rate at day 28 and at hospital discharge was 29.6% and 34.9% for mild ARDS, 35.2% and 40.3% for moderate and 40.9% and 46.1% for severe, respectively
Mortality is higher for ARDS with DAD (71.9%) than ARDS without DAD (45.5%) (Crit Care 2015;19:228, PLoS One 2017;12:e0180018, Chest 2016;149:1155)
Prognosis of ARDS patients has improved over the last decade (Chest 2008;133:1120)

Case reports

31 year old man with ARDS / DAD and eosinophilic pneumonia due to amphetamine smoking (Chin J Physiol 2014;57:295)
41 year old woman died of ARDS / DAD due to influenza A virus infection (Jpn J Infect Dis 2010;63:72)
43 year old man died of ARDS due to amyopathic dermatomyositis (Case Rep Crit Care 2016;2016:7379829)
45 year old woman died of ARDS / DAD due to rabies (Kaohsiung J Med Sci 2006;22:94)
49 year old man died of ARDS / DAD due to EBV positive diffuse large B cell lymphoma (Int J Clin Exp Pathol 2014;7:1742)
72 year old woman died of ARDS / DAD due to scrub typhus (J Korean Med Sci 2000;15:343)
72 year old man died of ARDS / DAD due to influenza B virus infection (Respirol Case Rep 2015;3:61)
75 year old man died of ARDS / DAD due to gemcitabine chemotoxicity (Intern Med 2003;42:1022)
77 year old woman died of ARDS / DAD due to acute interstitial pneumonia (Case Rep Med 2011;2011:628743)

Treatment

Treatment for the original insult
Oxygen therapy for respiratory failure (Lancet 2016;388:2416)
- Mechanical ventilation
  - PEEP or CPAP ≥ 5 cm H₂O
  - With / without neuromuscular blockade, prone position and ECMO
Supportive care
- Fluid management
- Pharmacotherapy
  - Glucocorticoid
  - Anticoagulant

Clinical images

Images hosted on other servers:

Chest radiograph

Exudative phase

Changes in ARDS

Chest CT

Exudative phase

Proliferative / organizing phase

Fibrotic phase

Changes in ARDS

Gross description

Dark blue lungs with dots of hemorrhage on pleural surface
Heavy and firm due to edema and fibrosis

Gross images

Images hosted on other servers:

Collection of Dr. Yale Rosen

DAD images

Congestive phase

Microscopic (histologic) description

Exudative phase
- Alveolar change (Am J Pathol 1976;85:209)
  - Hyaline membranes on alveolar duct or sacs
  - Interstitial and intra-alveolar edema
  - Collapsed alveoli
- Epithelial change
  - Denudation and necrosis of type I pneumocytes
- Vascular change
  - Necrosis of endothelial cells
  - Neutrophil aggregation
  - Micro thromboembolism
  - Hemorrhage
Proliferative / organizing phase (Arch Pathol Lab Med 2010;134:719)
- Alveolar change
  - Organizing or remnants of hyaline membrane
  - Interstitial and intra-alveolar proliferation of fibroblasts / myofibroblasts
  - Lymphocytic infiltration
- Epithelial change
  - Proliferation of type II pneumocyte
- Vascular change
  - Endothelial injury and thromboembolism in arteries / arterioles
Fibrosis phase (Clin Chest Med 2000;21:435)
- Alveolar change
  - Diffuse collagenous fibrosis
  - Microscopic honeycomb-like change
  - Traction bronchiolectasis
- Epithelial change
  - Squamous cell hyperplasia
- Vascular change (N Engl J Med 2000;342:1334)
  - Remodeling of arteries
  - Fibrosis in intima
  - Thickening of media
Others
- May have superimposed pneumonia
- Fibrin deposition
- Organizing pneumonia; aggregated fibroblasts with bluish extracellular matrix
  - DAD with prominent organizing pneumonia is also called "organizing DAD"

Microscopic (histologic) images

Scroll to see all images:

Images hosted on PathOut server:

Contributed by Akira Yoshikawa

Case 1: DAD of proliferative / organizing to fibrotic phase
Clinical manifestation: ARDS; dermatological manifestations such as mechanic hands, Gottron papules and photosensitivity; positivity for serum anti MDA5 antibody

Biopsy from S5

Biopsy from S9

Case 2: DAD of fibrotic phase; hard to rule out acute exacerbation of IPF
Clinical manifestation: acute respiratory failure (ARDS?); history of frequent fever; antinuclear antibody (80x)

Biopsy No. 1

Biopsy No. 2

Case 3: Organizing DAD
Clinical manifestation: ARDS; mechanic hands, Raynaud phenomenon, nailfold capillary change; negative for autoimmune antibodies

Biopsy from S5

Images hosted on other servers:

DAD in exudative and proliferative / organizing phase

Collapsed alveoli

Immature lung

Exudative phase

Hyaline membranes

Proliferative / organizing phase

Fibroblastic proliferation with remnants of hyaline membranes

Type II pneumocyte hyperplasia

Organizing DAD

Collection of Dr. Yale Rosen

Exudative phase

Hyaline membrane

Hyaline membrane and deposition of fibrin

Proliferative / organizing phase

Fibroblastic proliferation with remnants of hyaline membrane

Type II
pneumocyte
hyperplasia and
hyaline membrane

Organizing

Cytology description

Bronchoalveolar lavage (BAL) fluid
- Increased neutrophils in ARDS
- Helpful for the diagnosis of underlying disease

Positive stains

Fiber staining (e.g. elastic / van Gieson) is helpful to evaluate fibrosis
Giemsa, Grocott's methenamine silver (GMS) and Ziehl-Neelsen stains are helpful to identify pathogens
Immunohistochemistry (not of practical utility)
- Cytokeratin highlights collapsed alveoli
- Ki67 shows proliferation of fibroblast and epithelial cells (Hum Pathol 2009;40:1182)

Electron microscopy description

Changes in epithelium, endothelium and interstitium can be seen (N Engl J Med 2000;342:1334)
- Exudative phase
  - Vacuolization in damaged endothelial cells
  - Replacement of epithelial cells by hyaline membrane on the basement membrane
- Proliferative / organizing and fibrotic phases
  - Re-epithelialization of type II pneumocytes with microvilli and lamellar bodies with surfactant
  - Flattening of cytoplasm and loss of lamellar bodies and microvilli of type II pneumocyte, indicating transformation to type I pneumocyte
  - Collagen deposition

Videos

Histology of DAD

Differential diagnosis

Acute interstitial pneumonia
- So called "Hamman-Rich syndrome" or "idiopathic DAD"
- Lack of clinical criteria of ARDS
Cardiogenic pulmonary edema
- BNP ≥ 1200 pg/ml
- Congestive heart failure on echocardiograph
- Right heart catheterization is now not recommended due to negative influence to prognosis
Cryptogenic organizing pneumonia
- Migration of cardiac shadow
- Good response to corticosteroids
Drug induced lung injury
- History of causative drug
- Remission of symptoms after withdrawal of the responsible drug
Eosinophilic pneumonitis
- Current smoker or history of particle inhalation
- Eosinophilia ( > 25%) in BAL
- Good response to corticosteroids
Hypersensitivity pneumonitis
- History of antigen exposure
- Remission of symptoms after removal of the causative antigen
- Lymphocytosis ( > 30%) in BAL
- Diffuse centrilobular nodular shadow with ground glass opacity usually in upper lobes
Lymphangitic carcinomatosis
- Known malignancy
- Tumor cells in BAL or biopsy specimen
Miliary tuberculosis
- Diffuse nodular shadow ( ≤ 3 mm) involving whole lobes
- Mycobacterium tuberculosis in BAL or biopsy specimen
Usual interstitial pneumonia / idiopathic pulmonary fibrosis (UIP / IPF)
- Acute exacerbation of IPF and DAD are clinically and morphologically similar
- IPF shows chronic and dense collagen fibrosis with smooth muscle hyperplasia, while fibrosis in DAD is not so dense and usually lacks smooth muscle hyperplasia

Additional references

Board review style question #1

Which of the following findings is most suggestive for ARDS / DAD?

Bacterial pneumonia
Diffuse collagenous fibrosis
Hyaline membranes
Onset of respiratory failure 1 week after cardiac surgery
Organizing pneumonia

Board review answer #1

C. Hyaline membranes